The present invention is novel compounds which are a 5-hydroxy-2-pyrimidinylmethylene derivative and pharmaceutically acceptable acid addition or base salt thereof, pharmaceutical composition and method of use therefor. The invention compounds are found to have activity as inhibitors of one or both 5-lipoxygenase and cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever, and particularly rheumatoid arthritis, osteoarthritis, other inflammatory conditions, psoriasis, allergic diseases, asthma, inflammatory bowel disease, GI ulcers, cardiovascular conditions, including ischemic heart disease and atherosclerosis, and ischemia-induced cell damage, particularly brain damage caused by stroke. They can also be used topically for treating acne, sunburn, psoriasis, and eczema. Also included are leukotriene-mediated pulmonary, gastrointestinal, inflammatory, dermatological, and cardiovascular conditions. The disclosed compounds also have utility as antioxidants. The preferred method of use for the present invention is in treating inflammatory conditions. Thus, the present invention is also a pharmaceutical composition or method of manufacturing a pharmaceutical composition for the use of treating the noted conditions.
3,5-Ditertiarybutyl-4-hydoxyphenylmethylidene derivatives of thiazolidinones, oxazolidinones, and imidazolidinones are known to provide activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase.
See U.S. application Ser. No. 07/702,132, filed May 13, 1991, now pending; U.S. application Ser. No. 07/640,711, filed Jan. 18, 1991, now pending; and U.S. application Ser. No. 07/426,814, filed Oct. 30, 1989, now pending which is a continuation in part of U.S. application Ser. No. 07/277,171, filed Nov. 29, 1988, now abandoned. U.S. Ser. No. 07/426,814, U.S. Ser. No. 07/702,132, and U.S. Ser. No. 07/640,711 disclose numerous references having 3,5-ditertiarybutyl-4-hydroxy-benzylidenes and are incorporated by reference therefor. Pyrimidine is not noted in these references. Structure activity relationships of certain ditertiarybutylphenols and homologs thereof are discussed by Lazer, E. S., et al in "Effect of Structure on Potency and Selectivity in 2,6-Disubstituted-4-(2-Arylethenyl)phenol Lipoxygenase Inhibitors of J. Med. Chem. 1990, 33, 1892-1998. Again, pyrimidines are not noted in this reference and so compounds therein differ from the present invention.
An orotic aldehyde condensed with 3-(R-substituted)rhodanines is disclosed in CA89(15) 129478d and CA89(13)1093332 useful for complexing selected metal ions. The disclosed formula includes ##STR1##
These differ from the present invention by the position of substituents and number of hydroxys on the pyrimidine ring.
Numerous references disclose 2-amino-5-hydroxy pyrimidines. Compounds having other N containing groups in place of the amino group are also disclosed, however in each such compound all attachments are at the N of the pyrimidinyl moiety. Such disclosed pyrimidines may also be substituted at the 4- and/or 6-positions with various groups including alkyls. No reference shows 5-hydroxy together with the methylene heterocyclic group in the 2-position as now found in the present invention. For example, UK patent application number 2045736 and the Bioch. J. 1951, 48, p. 400 show the simple 2-amino-5-hydroxy-4,6-dimethylpyrimidine. Other substituted 2-aminopyrimidines are shown in European patent application numbers 89312736.5 and 86305466.4 (equivalent to U.S. Pat. No. 4,711,888), European publication numbers 319170, 233416, 164204, and U.S. Pat. Nos. 4,859,679 and 4,940,712.
Japanese Application No. 1,216,978 discloses 2-arylpyrimidines but differs from the present invention, that requires the 5-hydroxy substituent and methyleneheterocyclic substituent.
Pyrimidinylmethylene compounds have been described in CA 89(15)1294786 and CA 89(13)1093332 but differ in position of substituents and number of hydroxys.
5-OH pyrimidines have been described but none has the methylene heterocycle substituent at the 2-position.
Further, although French Application No. 1,476,534 presents a generic scope including various 2-substituted pyrimidines this French application differs from the present invention by failing to provide the present invention substituent combinations.
The disclosures in Chem. Ber. (1960), p. 1998-2001 and in The Indian Journal of Chemistry, Vol. 24B, May 1985, pp. 535-538, showing oxazole to pyrimidine ring transformations and the disclosure in Chemical Reviews 1975, Vol. 75, No. 4, pp. 207 and 412 showing a preparation of an oxazole and subsequent transformation to pyrimidine all show a synthesis and product having substituents in the 4- and 6-positions. These differ from the present invention by the failure to show a methylidene bridge between the heterocyclic ring.
In summary, the references of record show neither the present 2-substituent nor combinations of 4- and 6-substituents with a 5-hydroxy group and combinations of these with a methyleneheterocyclic group.
Thus, the references noted above differ from the present 5-hydroxy-2-pyrimidinylmethylidene or 4,6-dilower alkyl-5-hydroxy-2-pyrimidinyl methyleneheterocycles.